An inflammatory response is a process in which defensive cells are produced on route to an infectious source and ensure the elimination of the cause there. Different mediator substances are released in this process, contributing to the elimination but also creating the inflammation symptoms. In cases of faulty regulation of the reaction, these symptoms may cause most of the damage and/or may be the source of disease in general (e.g., in the case of allergies). A differentiation may also be made between acute inflammations (such as sepsis) and latent chronic inflammations (such as rheumatism). Inflammations may also be artificially induced, e.g., in organ transplants, which may ultimately result in rejection of the foreign organ. Inflammations may also be induced as an adverse effect due to certain medications.
In all these states, an artificial regulation of the immune response may be appropriate either as the main treatment or to nearly relieve symptoms.
During an inflammation, a number of cytokines may play a definite role in the progression of an immune response. Activated CD4-T cells produce interleukin-2, which is essential for activation of CD8-T cells as well as B cells. In addition, CD4-T cells produce other cytokines such as IFN-gamma, which enhances macrophage activity. TFN-alpha regulates the activity of different immune cells and may stimulate cell death, cell proliferation, cell differentiation, and secretion of other cytokines. It plays a triggering role in symptoms such as fever in particular.
One goal of the present invention is to make available an immune system regulator, in particular for treatment of inflammations.
The present invention therefore relates to a protein or a nucleic acid encoding the protein, where the protein is ACE2, for therapeutic treatment or prevention of an inflammation (or inflammatory diseases). Likewise, the present invention relates to the use of an ACE2 protein or an ACE2-encoding nucleic acid for production of a pharmaceutical composition for treatment or prevention of an inflammation. This likewise provides for the use of ACE2 protein or an ACE2-encoding nucleic acid for immunomodulation in a patient, such as treatment or prevention of an inflammation.
Angiotensin-converting enzyme 2 (ACE2) is an essential enzyme of the renin-angiotensin-aldosterone system, which is expressed as a membrane-anchored glycoprotein on various organs such as the heart, kidneys, liver, and lungs, but also on blood vessels.
ACE2 was discovered in 1997 as an ACE-homologous enzyme (GenBank Acc.: BAB40370, encoded by a nucleic acid with the sequence according to GenBank Acc.: AB046569). Initially it was thought to have the same enzymatic activity as ACE (U.S. Pat. No. 6,989,363). Only later was it discovered that ACE2 has a completely different mechanism of action than ACE and is even antagonistic to it (WO 2004/000367). ACE2 is a carboxypeptidase which cleaves numerous peptide substrates with great differences in selectivity and activity. ACE2 is also a cellular binding partner of SARS coronaviruses. Downregulation of ACE2 or administration of ACE2 to block virus receptors can therefore reduce susceptibility of ACE2-presenting cells (WO 2006/122819, Lang et al., Virology (2006) 353 (2): 474, Abstract). The functions described for ACE2 include mainly the conversion of Ang II to Ang 1-7, where the substrate and the product of this reaction have antagonistic properties. Ang II has essentially vasoconstrictive and hypotensive effects. Ang 1-7 has vasodilating effects and a protective effect in diseases of the heart, lungs, and kidneys (WO 2004/000367).